Photodynamic therapy (PDT) is an ancient concept and has been described and utilized over 30 centuries ago. The therapy was used in ancient times for the treatment of vitiligo in India, China and Egypt. In the last century, ultraviolet (UV) radiation was successfully used in the treatment of lupus vulgaris, a type of skin tuberculosis endemic in the Scandinavian countries.
PDT usually involves the administration of one or more photoactive agents to the subject to be treated followed by exposing the specific target location or target organ of the subject to light. Thus, for example, upon illumination, Methylene Blue has been used to kill Trichoderma Viride, a common fungus, outside the body. Similarly, acridine orange, as well as Methylene Blue, kills blood fluke Schistosoma mansoni, in vitro, upon exposure to light. P. S. Lacaz and J. C. E. Holanda, Bol. Acad. Nac. Med. (Brazil) 145: 43 (1974), Chem Abstr. 86:134166. Likewise, larvae of Anopheles mosquitoes are killed by the simultaneous exposure to photoactive dyes and light. A Barbieri, Accion fotodynamica de la luz. Riv. Malariol, 7:456 (1928); H. Schildmacher, Biol. Zentr. 69:468 (1950).
PDT has been used to neutralize externally the toxicity of many snake venom without significantly altering their antigenicity so that they can still be used to manufacture antibodies for the snake venom W. F. Kocholaty, J. C. Goetz, et al., Toxicon 5:153 (1968). Similar results have been reported for some animal viruses. Thus, utilizing similar technique, vaccines, including influenza vaccines, have been prepared. J. D. Spikes and R. Livingston, Adv. Radiat. Biol. 3:29 (1969); C. V. Hanson, in "Medical Virology," Proc. Int'l Symp. 2:45, Elsevier (1983). Likewise, influenza or encephalomyelitis viruses externally added to contaminate human blood plasma are inactivated by light in the presence of toluidine blue dye without significant alteration to the properties of plasma proteins. F. Heinmets, J. R. Kingston and C. W. Hiatt, Walter Reed Army Institute of Research Report 53-55:1 (1955).
Extracorporeal PDT, utilizing light and psoralen dyes, has also been reported for the treatment of cutaneous T-cell lymphoma. Psoralen dyes in the presence of light have also been used for the treatment of vitiligo. T. B. Fitzpatrick and M. A. Pathak, J. Invest. Dermatil. 32:229 (1959); A. V. Benedetto, Cutis 20:469 (1977). Skin tumors have been treated with the simultaneous exposure of the tumors to both eosin dyes and light. H. V. Tappeiner and A. Jesionek, Munch. Me. Wochenschr. 50:2042 (1903).
In the early 40's, it was observed that hematoporphyrin derivative (hereinafter Hpd) preferentially accumulated in tumors and lymph nodes. H. Auler and G. Banzer, Z. Krebforsch. 53:65 (1942). As a result, methods have been developed to capitalize on the unique property of Hpd as a tumor marker in the detection and localization of different forms of cancer cells. E. G. King, et al., Hematoporphyrin Derivative as a Tumor Marker in the Detection and Localization of Pulmonary Malignancy, in Recent Results in Cancer Research. Vol. 82, Springer-Verlag, Berlin-Heidelberg, 1982, 90; R. D. Benson, et al., Mayo Clinic Proc. 57:548 (1982).
Although the unique photodynamic properties of Hpd, as well as its unique preferential affinity toward tumor cells, had long been known, it was more than half a century later that the potential of using Hpd to selectively destroy tumor cells was explored. In 1966, Lipson and co-workers reported treating one case of recurrent breast cancer using a combination of Hpd and light. M. S. Lipson, M. J. Gray and E. J. Baldes, Proc. 9th Intl. Cancer Congr., p. 393 (1966). The use of light in the presence of Hpd to selectively destroy tumor cells in human has been reviewed by Dougherty et. al. T. J. Dougherty, et al., Photoradiation Therapy: Clinical and Drug Advances. In Porphyrin Photosensitization, D. Kessel and T. J. Dougherty, Eds. Plenum Press, N.Y., pp. 3-13, 1983.
U.S. Pat. No. 4,649,151 teaches the preparation and purification of porphyrin-type drugs. The patent also teaches the diagnosis and destruction of cancer cells with porphyrin-type drugs. In treating humans or other mammals with the drugs, light must be irradiated on the cancer cells in such a position as to uniformly illuminate the cancer cells. When cancer cells, having the porphyrin-type drugs associated therewith, are illuminated with light, the drugs are activated and thus causing the destruction of the cancer cells by a mechanism not completely understood yet. The patent also discloses several apparatus for transmitting light to different parts of the body.
U.S. Pat. No. 4,614,190 discloses that while a dye such as Hpd is being held within the tumor cells in the body, the activation of the dye is accomplished by pulsed electromagnetic radiation.
U.S. Pat. No. 4,727,027 teaches the inactivation of pathogenic biological microorganisms by simultaneous treatment with furocoumarins and a long wavelength ultraviolet light under conditions which limit the availability of oxygen and other reactive species.
U.S. Pat. No. 4,684,521 teaches a chemical agent for the reduction of the population of a selected blood constituent having receptor sites. The invention uses a photoactive agent physically incorporate within or chemically bound to a carrier molecule. The carrier molecule has a strong affinity for the receptor sites on the blood constituent. When activated by Ultraviolet ("UV") radiation, the photoactive agent bound to the carrier molecule interferes with the metabolism of the selected blood constituent.
U.S. Pat. No. 4,612,322 discloses a method and system for externally treating human blood to reduce the functioning lymphocyte population in the blood system. According to the method, blood is treated with a photoactive agent and simultaneously irradiated with UV radiation outside the body.
U.S. Pat. No. 4,708,715 teaches a removable UV light array assembly for use in a patient system wherein photoactivatable agents, in contact with patient blood cells, are irradiated extracorporeally and then returned to the patient.
Cyanine dyes are members of another class of dyes that are selectively retained by tumor cells and certain vises. For example, Merocyanine 540, (commonly referred to as MC 540) has been used for light-induced tumor and viral chemotherapy. K. S. Gulliya, J. L. Matthews, J. W. Fay, and R. M. Dowben, Proc. SPIE-Intl. Soc. Opt. Engineering 84f7:163-65 (1987); K. S. Gulliya, S. Pervaiz, D. G. Nealon, and D. V. VanderMeulen, Proc. SPIE-Intl. Soc. Opt. Engineering 907:34-36 (1988); F. Sieber, Photochem. and Photobiol. 46:1035-42 (1987).
The emphasis on using a photoactive compound or dye as the photoactivating or light-activating compound in photoradiation of tumors or viruses is based on two important properties of the photoactive compound or dye. Firstly, the photoactive compound or dye is preferentially accumulated and retained to a higher degree in or around the target tumor or virus than in the surrounding normal body tissues. Secondly, after being retained in or around the tumor or virus, the photoactive compound or dye is properly photoactivated causing the destruction of tumor cells or virus with which the dye has associated. The destruction of tumor cells or virus occurs when they are simultaneously exposed to the dye and light of a suitable wavelength. The generally accepted mechanism of cell kill by photoactivated dye is that when activated by appropriate light, the dye undergoes an energy transfer process with oxygen to form a reactive singlet oxygen, which subsequently oxidizes and kills the cell or virus to which the dye has attached or associated as a substrate. K. R. Weishaupt, C. J. Gomer, and T. J. Dougherty, Cancer Res. 36:2326-29 (1976); F. Sieber, Photochem. and Photobiol. 46:1035-42 (1987).
The life-time of the extremely reactive singlet oxygen is extremely short, less than a fraction of microsecond. Hence, the currently accepted method of practicing PDT is to first let the photoactive compound bind to the target tumor cells or viruses, and then activate the bound photoactive compound. Thus, when the reactive singlet oxygen is generated from photoactivation, the target tumor cells or viruses that are in the close proximity to the activated dye and oxygen are destroyed. The normal cells do not preferentially accumulate the photoactive compound, hence generally very little reactive singlet oxygen is generated in their close proximity. Accordingly, the normal cells are generally spared from destruction by the photoactivated photoactive compound. T. J. Dougherty, et at., Photoradiation Therapy: Clinical and Drug Advances. In Porphyrin Photosensitization, D. Kessel and T. J. Dougherty, Eds. Plenum Press, N.Y., pp. 3-13, 1983.
It has been reported that dye such as MC 540 will undergo considerable photobleaching when being irradiated with a light source with the wavelength from about 320 to 600 nm. After about 70 minutes, the dye was decomposed as a result of direct oxidation and/or reaction with lipid peroxides. B. Kalyanaraman, J. B. Feix, F. Sieber, J. P. Thomas, and A. W. Girotti, Proc. Natl. Acad. Sci., U.S.A. 84:2999-3003 (1987). Similarly, irradiation of an aqueous solution of MC 540 with white light fitted with a 360-nm cutoff filter results in a colorless solution in about 20 min. N. S. Dixit and R. A. Mackay, J. Am. Chem. Soc. 105:2928-29 (1983). Other cyanine dyes also undergo photobleaching in solution. O. Valdes-Aguilera, L. Cincotta, J. Foley, and I. E. Kochevar, Photochem. Photobiol. 45:337-44 (1987). Consequently, samples of dye solution are always prepared freshly and in the dark.
As can be seen from the discussion above, PDT has one major limitation in practical utility, that is, in order to eradicate from the animal body the tumor cells or vises on which the photoactive compound or dye resides, such cells or virus must be exposed to an appropriate light source. Thus, to achieve the desired killing, one must find, if at all possible, the target tumor cells which have preferentially accumulated the photoactive compound, and then one must irradiate these target cells inside the animal body with a light source directly. If the tumor, such as solid tumor, is large enough and localized that it can been seen by naked eyes, then the dye can be injected into the tumor itself. There is still the problem of introducing light into the inner portions of the tumor. Moreover, during metastasis, the tumor cells or viruses have spread to other parts of the body and are no longer localized. The dilemma after the introduction of photoactive compound to the patient is: Where should the irradiation be given?. Even assuming that the malignant tumor cells can be localized and found in one particular body tissue or organ, many body tissues and internal organs where tumor cells or viruses have proliferated are nonetheless inaccessible to any light.
Another major limitation to PDT is that the light energy itself, in particular the ultraviolet light, is toxic and can be mutagenic to normal cells as well normal tissues. Thus, many photoactive compounds that can be activated best by ultraviolet light cannot be used in the clinic because the ultraviolet light required for the activation of the compounds would be exceedingly harmful to the surrounding normal tissues and the normal cells.